The ultimate goal of this Program is to induce and maintain immunologic tolerance in organ transplant patients. To this end, we propose to define the mechanism of action of HLA derived peptides and to optimize them for clinical use. Project 1 focuses on further elucidation of the mechanism of action of the HLA-B2702 derived peptide that has already been shown to inhibit T lymphocyte responses both in vitro and in vivo, and has been advanced to phase II clinical trials. In aim 1, a 46kD protein that is decreased in phosporylation upon T cell activation in the presence of presence of peptide will be identified and characterized, and the signal transduction pathway involved will be investigated. Intracellular localization of peptide will be characterized by microscopy. In aim 2, heat shock protein 70 family members that bind this peptide will be further characterized and new ligand(s) will be identified using the yeast two hybrid approach. In aim 3, peptides will be optimized for use in vivo. The use of D-amino acids, continuous infusion or release, local delivery, and non-peptidic analogs will be explored. This Project parallels Project 2, which will investigate a class II derived peptide, relies on Project 3 for gene therapy approaches, and is heavily dependent on Core B for novel peptides.